Angiogenesis is necessary for growth and progression of injury of primary tumors and their metastases. Angiogenesis inhibitors discovered in this Program Project are in clinical trials, and the prognostic value of microvessel density in tumors is used in many medical centers. In the renewal of this Program Project, 7 investigators who work closely together, and whose laboratories are all on the same floor, will study the regulation of angiogenesis at the molecular and cellular levels and in tumor-bearing animals. Vascular endothelial growth factor (VEGF), produced by the majority of human tumors, will be investigated by characterization of a novel VEGF receptor and development of receptor neutralizing reagents (Klagsbrun). Vascular development and differentiation will be investigated by studying the role of specific VEGF isoforms, and by characterization of a novel gene which may be involved in endothelial differentiation (D'Amore). Mechanisms through which tissue inhibitors of metalloproteinases (TIMP) exert their anti-angiogenic effects will be studied by characterizing shifts in proteolytic balance in tumor cells and by functional analysis of different structural domains of the TIMPS (Moses). Focal adhesion complexes (FAC) between vascular endothelial cells (EC) and their extracellular matrix will be studied to determine how information is transmitted to the nucleus and how this is affected by angiogenesis inhibitors that are in clinical or pre-clinical application (Ingber). E-selectin, which is expressed in proliferating EC in angiogenic tissues, will be studied to determine the pathways for its up-regulation, to determine the stimulators and inhibitors inhibit, the motility of EC during angiogenesis will be studied (Zetter). A powerful new antiangiogenic protein, endostatin, will be produced in E.coli and used to regress human and animal tumor dormancy in mice, a model which closely resembles human tumor dormancy, will be investigated. Pre-clinical studies of "dormancy therapy" will be conducted (Folkman). The studies in this Program Project all focus on the development of a detailed understanding of the angiogenic process with the goal of applying this knowledge to current and future clinical applications.